Chlorphenoxamine

Alkylation of these as their sodium salts with the ubiquitous N-C2-chloroethyl)dimethylamine affords the desired antihistamines. There are thus obtained, respectively, mephenhydramine (23a) chlorphenoxamine (23b), and mebrophenhydramine (23c)Alkylation of the tertiary alcohol, 22b, with the pyrrolidine derivative, 24, affords meclastine (25). In much the same vein, reaction of 2-acetylpyridine with phenyImagnesium bromide gives the tertiary alcohol, 27. Alkylation in the usual way leads to the potent antihistamine, doxylamine (28). " ... 

N-p-Chlorobenzohydryl piperazine Hydroxyzine HCI o-Chlorobenzo nitrile Ketamine HCI o-Chlorobenzophenone Chlophedianol 4-Chlorobenzophenone Chlorphenoxamine HCI p-Chlorobenzoyl chloride Benoxaprofen... 

Dimethylamino ethyl chloride (cont d) Chlorphenoxamine HCI Dibenzepin HCI Moxisylyte Noxiptilin... 

C4H10CIN 107-99-3) see Bephenium hydroxynaphthoate Binedaline Brompheniramine Captodiame Carbinoxamine Chlorphenamine Chlorphenoxamine Cyclopentolate Dibenzepine Diltiazem Dimetindene Doxylamine Ethoheptazine Itopride hydrochloride Meclofenoxate Mepyramine Moxisylyte Normethadone Noxiptiline Pheniramine Phenyltoloxamine Tamoxifen Toremifene Trimethobenzamide Tripelennamine Zotepine... 

Ethers are stable toward hydrolysis, yet are hydrolyzed under severe conditions of acidity and temperature. Furthermore, the presence of certain moieties can decrease the high stability of ethers. In the case of aminoalkyl benzhydryl ethers of the general structure (aryl)2CH-0-(CH2)n-NRR, the decrease in stability becomes marked enough to be of pharmaceutical and even pharmacological relevance. This structural motif is a component of various drugs, including some well-known antihistamines and anticholinergics, e.g., diphenhydramine, orphenadrine, and chlorphenoxamine. 

Fig. 11.2. Mechanism of proton-catalyzed, hydrolysis of aminoalkyl benzhydryl ethers 11.24, e.g., diphenhydramine (R = R = H), orphenadrine (R = 2-Me, R = H), and chlorphenoxamine...

From these data, it can be estimated that chlorphenoxamine (11.24, R = 4-C1, R = Me) should hydrolyze ca. 17 times faster than diphenhydramine. This decreased stability appears sufficient to drive formation of detectable amounts of the benzhydrol metabolite (11.25, R = 4-C1, R = Me) in the stomach of patients dosed with chlorphenoxamine. Indeed, ether bond cleavage to form this and derived metabolites was a major pathway in humans [49], Whether the reaction was entirely nonenzymatic or resulted in part from oxidative O-dealkylation (Chapt. 7 in [50]) remains unknown. 

Clemastine, an antihistamine closely related to chlorphenoxamine in which the dimethylamino group is replaced by 1 -methylpyrrolidin-2-yl, appears to be comparable in stability to chlorphenoxamine. Indeed, cleavage of the ether was the dominant feature of metabolism in humans [51] [52], and, in fact, all metabolites recovered in humans were either the benzhydrol analogue or products of its further biotransformation. Here again, the ether cleavage pathway may be entirely or only partly nonenzymatic, although the extent of the reaction suggests an enzymatic contribution. 

Scheme 17. Syntheses of sila-mephenhydramine, sila-chlorphenoxamine, sila-clofenetamine, sila-mebrophenhydramine and sila-meflophenhydramine...

Si-CH20—C instead of Si-O-C) have been synthesized in a similar manner104,106, io8, io9, m, H4) Syntheses of the carbon analogues, demonstrated for mephen-hydramine (150a) and chlorphenoxamine (151a), were effected by different means (cf. Scheme 18) ... 

Sila-chlorphenoxamine (LD50 = 411.6 mg/kg) exhibits only 25% of acute toxicity (white mice, i.p.) of its carbon analogue (LD50 = 108.6 mg/kg)112). This observation could easily be explained by a rapid hydrolytic detoxication of the sila-pharma-con. 

Sila-mephenhydramine (150b), sila-chlorphenoxamine (151b) and sila-meflo-phenhydramine (154b) were found to exhibit antiarrhythmic activity on the isolated left auricle of the guinea pig. The silicon compounds lead to an increase of... 

Fig. 3. Dose-activity curves of chlorphenoxamine and sila-clilorphenoxamine...

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